3-81761400-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000158.4(GBE1):c.118C>A(p.Pro40Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00175 in 1,612,950 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P40S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0054 ( 7 hom., cov: 34)

Exomes 𝑓: 0.0014 ( 19 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 3.94

Variant links:

Genes affected

GBE1 (HGNC:4180): (1,4-alpha-glucan branching enzyme 1) The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]

GBE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008630902).

BP6

Variant 3-81761400-G-T is Benign according to our data. Variant chr3-81761400-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 255381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81761400-G-T is described in Lovd as [Likely_benign]. Variant chr3-81761400-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00543 (827/152372) while in subpopulation AFR AF = 0.0148 (617/41600). AF 95% confidence interval is 0.0139. There are 7 homozygotes in GnomAd4. There are 388 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBE1	NM_000158.4 link	c.118C>A	p.Pro40Thr	missense_variant	Exon 1 of 16	ENST00000429644.7	NP_000149.4	Q04446Q59ET0
GBE1	XR_007095662.1 link	n.246C>A		non_coding_transcript_exon_variant	Exon 1 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644.7 link	c.118C>A	p.Pro40Thr	missense_variant	Exon 1 of 16	1	NM_000158.4	ENSP00000410833.2		Q04446

Frequencies

GnomAD3 genomes

AF:

0.00537

AC:

817

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00477

Gnomad ASJ

AF:

0.0230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00253

AC:

625

AN:

247310

AF XY:

0.00246

show subpopulations

Gnomad AFR exome

AF:

0.0141

Gnomad AMR exome

AF:

0.00180

Gnomad ASJ exome

AF:

0.0255

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000690

Gnomad OTH exome

AF:

0.00266

GnomAD4 exome

AF:

0.00137

AC:

1997

AN:

1460578

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

1008

AN XY:

726584

show subpopulations

Gnomad4 AFR exome

AF:

0.0152

AC:

505

AN:

33280

Gnomad4 AMR exome

AF:

0.00201

AC:

AN:

44684

Gnomad4 ASJ exome

AF:

0.0244

AC:

637

AN:

26074

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39614

Gnomad4 SAS exome

AF:

0.0000348

AC:

AN:

86246

Gnomad4 FIN exome

AF:

0.0000375

AC:

AN:

53376

Gnomad4 NFE exome

AF:

0.000477

AC:

530

AN:

1111236

Gnomad4 Remaining exome

AF:

0.00360

AC:

217

AN:

60320

Heterozygous variant carriers

105

210

314

419

524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00543

AC:

827

AN:

152372

Hom.:

Cov.:

AF XY:

0.00521

AC XY:

388

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0148

AC:

0.0148317

AN:

0.0148317

Gnomad4 AMR

AF:

0.00477

AC:

0.00476688

AN:

0.00476688

Gnomad4 ASJ

AF:

0.0230

AC:

0.0230415

AN:

0.0230415

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000617

AC:

0.00061732

AN:

0.00061732

Gnomad4 OTH

AF:

0.00710

AC:

0.00709555

AN:

0.00709555

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00330

Hom.:

Bravo

AF:

0.00637

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.00168

AC:

ExAC

AF:

0.00233

AC:

282

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 15, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27790088, 26670585, 25133958, 31692161) -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GBE1: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Glycogen storage disease, type IV

Benign:4

Mar 06, 2017

Counsyl

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 29, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified

Benign:2

Feb 17, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease

Benign:1

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GBE1-related disorder

Benign:1

Jun 21, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Adult polyglucosan body disease

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

Eigen

Benign

0.015

Eigen_PC

Benign

0.097

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0086

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.9

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.092

Sift

Uncertain

0.018

Sift4G

Uncertain

0.032

Polyphen

0.047

Vest4

0.46

MVP

0.47

MPC

0.034

ClinPred

0.059

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.65

Mutation Taster

=98/2

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over